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Four‐dimensional quantitative structure‐activity analysis of 1,4‐naphthoquinone derivatives tested against HL‐60 human promyelocytic leukemia cells
Journal of Chemometrics ( IF 2.4 ) Pub Date : 2020-02-01 , DOI: 10.1002/cem.3131
Maria Cristina A. Costa 1 , Pedro O. Mariz Carvalho 1 , Márcia M. C. Ferreira 1
Affiliation  

Four‐dimensional quantitative structure‐activity relationship (4D‐QSAR) models were developed to predict biological activity of 1,4‐naphthoquinones derivatives tested against human HL‐60 leukemic cells, in order to better investigate the action mode of these compounds. Quinones can generate reactive oxygen species (ROS) through the activation by the cytochrome P450 and P450 reductase enzymes acting as anticancer agents. Molecular dynamics (MD) simulations were performed in the 3D optimized geometries, and the field descriptors were calculated. Partial least squares (PLS) regression method was applied to build the QSAR model, which presented the following statistics, with two factors and explaining 51.11% of total variance: R2 = 0.83; SEC = 0.28; Q2 = 0.77; SEV = 0.31. For external validation, the results were R2pred = 0.76 and SEP = 0.30. Among the nine Coulomb (C) and Lennard‐Jones (LJ) descriptors selected by the model, one of them, C13838, is located close to quinone oxygens involved in the production of radical anions (O2−·) and to hydroxyl in position 5 that may stabilize catalytically important water molecules. The negative LJ descriptors around R1 and R2 substituents might indicate that apolar substituents in these regions are unfavorable to the activity. Coulomb descriptors located at the vicinities of the substituent R2 gave information about the bioactive conformation.

中文翻译:

针对 HL-60 人早幼粒细胞白血病细胞测试的 1,4-萘醌衍生物的四维定量构效分析

开发了四维定量构效关系 (4D-QSAR) 模型来预测 1,4-萘醌衍生物对人 HL-60 白血病细胞的生物活性,以更好地研究这些化合物的作用模式。醌可以通过作为抗癌剂的细胞色素 P450 和 P450 还原酶的激活产生活性氧 (ROS)。在 3D 优化几何结构中进行分子动力学 (MD) 模拟,并计算场描述符。采用偏最小二乘(PLS)回归方法构建QSAR模型,该模型呈现以下统计量,有两个因素,解释总方差的51.11%:R2 = 0.83;秒 = 0.28; Q2 = 0.77;SEV = 0.31。对于外部验证,结果为 R2pred = 0.76 和 SEP = 0.30。在模型选择的九个库仑 (C) 和伦纳德-琼斯 (LJ) 描述符中,其中一个 C13838 靠近参与自由基阴离子 (O2-·) 产生的醌氧和第 5 位的羟基这可以稳定具有催化作用的水分子。R1 和 R2 取代基周围的负 LJ 描述符可能表明这些区域中的非极性取代基不利于活性。位于取代基 R2 附近的库仑描述符提供了有关生物活性构象的信息。R1 和 R2 取代基周围的负 LJ 描述符可能表明这些区域中的非极性取代基不利于活性。位于取代基 R2 附近的库仑描述符提供了有关生物活性构象的信息。R1 和 R2 取代基周围的负 LJ 描述符可能表明这些区域中的非极性取代基对活性不利。位于取代基 R2 附近的库仑描述符提供了有关生物活性构象的信息。
更新日期:2020-02-01
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